Use of thiazole and thiadiazole compounds

ABSTRACT

The present invention relates to the use of thiazole and thiadiazole compounds of the following formula: ##STR1## where R 1 , A, B and Ar have the meanings stated in the description. The compounds according to the invention have a high affinity for the dopamine D 3  receptor and can therefore be used to treat disorders of the central nervous system.

The invention relates to the use of thiazole and thiadiazole compounds. Said compounds have valuable therapeutic properties and can be used to treat disorders which respond to dopamine D₃ receptor ligands.

Compounds which are of the type under discussion here and have physiological activities have been disclosed. Thus, U.S. Pat. No. 4,074,049 describes aminoalkylthiothiadiazoles which act as fungicides and blood platelet aggregation inhibitors. JP-A-2 153 276 describes similar compounds which are used to treat liver disorders.

GB-A-1 053 085 describes aminoalkylthiadiazoles which show antitussive, analgesic, antipyretic and hypoglycemic effects. U.S. Pat. No. 3,717,651 describes 5-mercapto-substituted thiazoles which have herbicidal properties.

WO 89/11 476 describes substituted 2-aminothiazoles as dopaminergic agents which can be used, inter alia, for treating psychoses and disorders of the CNS.

WO 92/22 540 describes aminoalkyl-substituted 5-mercaptothiazoles of the formula: ##STR2## where R¹ is H, C₁ -C₅ -alkyl, unsubstituted or substituted phenyl or thienyl; n is 2-6; and A is ##STR3## where Ar is a phenyl ring which is unsubstituted or substituted once by C₁ -C₅ -alkyl, C₁ -C₅ -alkoxy, amino, halogen, nitro, hydroxyl, trifluoromethyl or cyano, or a pyridyl, pyrimidinyl or thienyl radical. These compounds can be used to treat disorders of the central nervous system, eg. Parkinsonism, schizophrenia and disorders associated with elevated blood pressure.

WO 92/22 542 describes the corresponding 2-amino-5-mercapto-1,3,4-thiadiazole derivatives which can likewise be used to treat disorders of the central nervous system and disorders associated with elevated blood pressure.

WO 92/22 541 describes corresponding 2-amino-1,3,4-thiadiazole derivatives where the alkylene chain is linked directly, not via a sulfur atom, to the thiadiazole residue. These compounds can also be used for treating disorders of the central nervous system and disorders associated with elevated blood pressure.

WO 93/21 179 describes 1-aryl-4-(ω-amido-1-alkyl and ω-imido-1-alkyl)piperazine compounds. These compounds are dopamine D₂ receptor antagonists and 5-HT_(1A) receptor agonists. They can be used as antipsychotic agents, for example for treating schizophrenia.

Neurons receive their information inter alia via G protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of them is dopamine.

Confirmed findings on the presence of dopamine and its physiological function as neurotransmitter have been published. Cells which respond to dopamine are connected with the etiology of schizophrenia and Parkinson's disease. These and other disorders are treated with drugs which interact with dopamine receptors.

By 1990, two subtypes of dopamine receptors had been clearly defined pharmacologically, namely D₁ and D₂ receptors.

Sokoloff et al., Nature 1990, 347: 146-151, found a third subtype, namely D₃ receptors. They are expressed mainly in the limbic system. The D₃ receptors differ structurally from the D₁ and D₂ receptors in about half the amino-acid residues.

The effect of neuroleptics has generally been ascribed to their affinity for D₂ receptors. Recent receptor-binding studies have confirmed this. According to these, most dopamine antagonists, like neuroleptics, have high affinity for D₂ receptors but only low affinity for D₃ receptors.

The prior art compounds described above are such D₂ receptor agonists or antagonists.

We have now found, surprisingly, that the compounds according to the invention have a high affinity for the dopamine D₃ receptor and only a low affinity for the D₂ receptor. They are thus selective D₃ ligands.

The present invention therefore relates to the use of thiazole and thiadiazole compounds of the formula I: ##STR4## where A is a straight-chain or branched C₁ -C₁₈ -alkylene group which may comprise at least one group selected from O, S, NR³, CONR³, NR³ CO, COO, OCO or a double or triple bond,

B is a radical of the formula: ##STR5## R¹ is H, halogen, CN, CO₂ R², NR² R³, OR³, CF₃ or C₁ -C₈ -alkyl, which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen;

R² is H, C₁ -C₈ -alkyl, which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen or phenyl-C₁ -C₈ -alkyl;

R³ has the meanings indicated for R² or is COR² or CO₂ R² ;

X is N or CR⁴ where R⁴ is H, C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, or is phenyl which is unsubstituted or substituted by halogen, CF₃, C₁ -C₈ -alkyl or C₁ -C₈ -alkoxy;

Ar is phenyl, pyridyl, pyrimidyl or triazinyl, where Ar may have from one to four substituents which are selected, independently of one another, from H, OR³, C₁ -C₈ -alkyl, C₂ -C₈ -alkenyl, C₂ -C₈ -alkynyl, halogen, CN, CO₂ R², NO₂, SO₂ R², SO₃ R², NR² R³, SO₂ NR² R³, SR², CF₃, CH₂, a 5- or 6-membered carbocyclic aromatic or non-aromatic ring and a 5- or 6-membered heterocyclic aromatic or non-aromatic ring having 1 to 3 hetero atoms selected from O, S and N, where the carbocyclic or the heterocyclic ring is unsubstituted or substituted by C₁ -C₈ -alkyl, halogen, OC₁ -C₈ -alkyl, OH, NO₂ or CF₃ and where Ar may also be fused to a carbocyclic or heterocyclic ring of the type defined above,

and the salts thereof with physiologically tolerated acids for producing a pharmaceutical composition for treating disorders which respond to dopamine D₃ receptor antagonists or agonists.

The compounds used according to the invention are selective dopamine D₃ receptor ligands which intervene regioselectively in the limbic system and, because of their low affinity for the D₂ receptor, have fewer side effects than classical neuroleptics. The compounds can therefore be used to treat disorders which respond to dopamine D₃ receptor antagonists or agonists, eg. for treating disorders of the central nervous system, in particular schizophrenia, depression, neuroses and psychoses. They can additionally be used to treat sleep disorders and nausea and as antihistamines.

Within the scope of the present invention, the following terms have the meanings indicated below:

Alkyl (also in radicals such as alkoxy, alkylamino etc.) means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and, in particular, 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of one another, from among OH and OC₁ -C₈ -alkyl.

Examples of an alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl etc.

Alkylene stands for straight-chain or branched radicals having, preferably, 2 to 14 carbon atoms, particularly preferably 3 to 12 carbon atoms and, in particular, 7 to 12 carbon atoms.

The alkylene groups may comprise at least one of the abovementioned groups. This can--just like the double or triple bond mentioned--be arranged in the alkylene chain at any point or at the end of the chain so that it connects the chain to the thiazole or thiadiazole residue. The latter is preferred. When the alkylene group comprises a double or triple bond, it has at least three carbon atoms in the chain.

Halogen is F, Cl, Br, I and, in particular, F, Cl, Br.

R¹ is preferably H, OR³ or NR² R³, where R² and R³ are, independently of one another, H or C₁ -C₈ -alkyl.

Ar can have one, two, three or four substituents.

They are preferably selected, independently of one another, from H, C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen, or phenyl, naphthyl, C₃ -C₈ -cycloalkyl, a 5- or 6-membered heterocyclic aromatic or nonaromatic radical with 1 to 3 hetero atoms selected from O, N and S, CHF₂, CF₃, halogen, NO₂, CN, OR³ or SR², where R² and R³ have the abovementioned meanings.

If one of the substituents of Ar is C₁ -C₈ -alkyl, a branched radical, in particular the isopropyl or t-butyl group, is preferred.

Ar preferably has at least one substituent and is, in particular, ##STR6## where D¹, D² and D³ are, independently of one another, CR or N, and R, Y and Z are H or have the meanings indicated above or below.

Ar is preferably unsubstituted or substituted phenyl, 2-, 3- or 4-pyridinyl or 2-, 4(6)- or 5-pyrimidinyl.

When one of the substituents of Ar is a 5- or 6-membered heterocyclic ring, examples thereof are a pyrrolidine, piperidine, morpholine, piperazine, pyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole or thiadiazole residue.

When one of the substituents of Ar is a carbocyclic radical, it is, in particular, a phenyl, cyclopentyl or cyclohexyl radical.

When Ar is fused to a carbocyclic or heterocyclic radical, Ar is, in particular, a naphthalene, di- or tetrahydronaphthalene, quinoline, di- or tetrahydroquinoline, indole, dihydroindole, benzimidazole, benzothiazole, benzothiadiazole, benzopyrrole or benzotriazole residue.

A preferred embodiment comprises the compounds of the formula I where A is C₃ -C₁₄ -alkylene, in particular C₃ -C₁₂ -alkylene, which may comprise at least one group selected from O, S, NR³ and a double or triple bond.

Another preferred embodiment comprises the use of compounds of the formula I where

R¹ is H, OR³ or NR² R³, where R² and R³ are, independently of one another, H, C₁ -C₈ -alkyl or phenyl-C₁ -C₈ -alkyl,

R⁴ is H or C₁ -C₈ -alkyl when X is CR⁴ ;

A is C₃ -C₁₂ -alkylene which may comprise at least one group selected from O, S, NR³ and a double or triple bond;

Ar is phenyl, pyrimidyl or pyridyl which may have one, two, three or four substituents which are selected, independently of one another, from H, C₁ -C₈ -alkyl which is unsubstituted or substituted by OH, OC₁ -C₈ -alkyl or halogen or phenyl, naphthyl, C₃ -C₈ -cycloalkyl, a 5- or 6-membered heterocyclic aromatic or nonaromatic radical with 1 to 3 hetero atoms selected from O, N and S, CHF₂, CF₃, halogen, NO₂, CN, OR³ or SR², where R² and R³ have the abovementioned meanings.

Particularly preferred compounds in this connection are those of the formula I where

B is ##STR7##

Another preferred embodiment is the use of the compounds of the formula I where

Ar is phenyl which has one, two, three or four substituents which are selected, independently of one another, from H, C₁ -C₈ -alkyl, phenyl, naphthyl, pyrrolyl, CHF₂, CF₃, halogen, NO₂, CN, OH, OC₁ -C₈ -alkyl, SH and SC₁ -C₈ -alkyl.

Ar is particularly preferably phenyl with one or two substituents in position 3 or position 3,5.

Another preferred embodiment is the use of compounds of the formula I where Ar is pyrimidinyl which has one to three substituents which are selected, independently of one another, from H, C₁ -C₈ -alkyl, C₃ -C₈ -cycloalkyl, phenyl, naphthyl, pyrrolyl, OH, OC₁ -C₈ -alkyl, CHF₂, CF₃ and halogen, or where Ar is pyridinyl which has one to four substituents which are selected, independently of one another, from H, C₁ -C₈ -alkyl, C₂ -C₈ -alkenyl, C₂ -C₈ -alkynyl, phenyl, naphthyl, pyrrolyl, OR, OC₁ -C₈ -alkyl, CHF₂, CF₃, CN and halogen.

The invention also relates to the compounds of the formula I where A is a straight-chain or branched C₇ -C₁₈ -alkylene group which may comprise a group which is selected from among O, S, NR³, CONR³, NR³ CO, COO, OCO or double or triple bond, and R¹, R³, B and Ar have the abovementioned meanings.

The invention also embraces the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung, Volume 10, pages 224 et seq., Birkhauser Verlag, Basel and Stuttgart, 1966.

The compounds of the formulae sic! I may have one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The invention also includes the tautomeric forms in each case.

The compounds of the formulae sic! I can be prepared by methods similar to conventional ones as described, for example, in Houben Weyl, "Handbuch der Organishen Chemie", Ernst Schaumann (Ed.), 4th Ed. Thieme Verlag, Stuttgart 1994, Volume Es/d, pages 189 et seq.; A. R. Katritzky, C. W. Rees (ed.) "Comprehensive Heterocyclic Chemistry", 1st Ed. and literature cited therein. The process for preparing the compounds comprises

i) reacting a compound of the general formula II: ##STR8## where Y¹ is a conventional leaving group, with a compound of the general formula III:

    H--B--Ar

ii) to prepare a compound of the formula I where A comprises an oxygen or sulfur atom or NR³,

a) reacting a compound of the general formula IV: ##STR9## where Z¹ is O, S or NR³, and A¹ is C₀ -C₁₈ -alkylene, with a compound of the general formula VI

    Y.sup.1 --A.sup.2 --B--Ar

where Y¹ has the abovementioned meanings, and A² is C₁ -C₁₈ -alkylene, where A¹ and A² together have 7 to 18 carbon atoms;

iii) to prepare a compound of the formula I where A comprises the group COO or CONR³ :

a) reacting a compound of the general formula VII: ##STR10## where Y² is OH, OC₁ -C₄ -alkyl, Cl or, together with CO, is an activated carboxyl group, and A¹ has the abovementioned meanings, with a compound of the formula VIII:

    Z.sup.1 --A.sup.2 --B--Ar

where A² has the abovementioned meanings, and Z¹ is OH or NHR³,

iv) to prepare a compound of the formula I where A comprises the group OCO or NR³ CO:

a) reacting a compound of the formula IV ##STR11## where Z¹ is O, or NR³, with a compound of the formula X:

    Y.sup.2 CO--A.sup.2 --B--Ar

where A² and Y² have the abovementioned meanings, and where R¹, R², A, B and Ar have the abovementioned meanings.

To treat the abovementioned disorders, the compounds according to the invention are administered in a conventional manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is about 10 to 1000 mg per patient and day on oral administration and about 1 to 500 mg per patient and day on parenteral administration.

The invention also relates to pharmaceutical compositions which contain the compounds according to the invention. These compositions are in the usual solid or liquid pharmaceutical administration forms, for example as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. The active substances can in these cases be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain the active substance in an amount from 1 to 99% by weight.

The following examples serve to explain the invention without limiting it.

EXAMPLE 1 ##STR12##

a) 2-Amino-5-(6-chlorohexylmercapto)-1,3,4-thiadiazole

5 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 7.5 g of 1,6-bromochlorohexane sic! and 4.07 g of triethylamine were refluxed in 100 ml of tetrahydrofuran for 1 hour. The mixture was filtered with suction, the filtrate was concentrated, and the residue was washed with water and then dried. 8.2 g (=91% yield) of product remained.

b) 2-Amino-5-(6-(3,5-dichlorophenylpiperazinyl)hexylmercapto)-1,3,4-thiadiazole) sic!

2.2 g of product from la), 2.08 g of 3,5-dichloro-phenylpiperazine and 1 g of triethylamine in 4 ml of DMF were heated at 100° C. for 1 hour. Water was added to the mixture and, after extracting 3 times with methylene chloride, drying over MgSO₄ and concentrating, the residue was purified by chromatography (mobile phase: CH₂ Cl/CH₃ OH sic!=9/1). 1.0 g (=25% yield) of product was obtained. Melting point: 130° C.

EXAMPLE 2 ##STR13##

a) 5-Amino-2-(6-bromohexyl)-1,3,4-thiadiazole

5 g of 7-bromoheptanoic acid and 2.17 g of thiosemicarbazide were introduced into 50 ml of dioxane at 90° C. and, at this temperature, 4.0 g of POCl₃ were added dropwise. The mixture was then stirred at 90° C. for 1 hour. Then water was added to the mixture, and extraction 3 times with methylene chloride, drying over MgSO₄ and concentration were carried out. 6.1 g (=96% yield) of product were obtained as residue.

b) 2.5 g of product 2a), 2.18 g of u-trifluoromethylphenylpiperazine and 1.92 g of triethylamine in 3 ml of DMF were stirred at 100° C. for 1 hour. Workup took place as for lb). 1.4 g (=36% yield) of product were obtained. Melting point: 134-136° C.

The compounds indicated in Tables 1 to 3 below were prepared in a similar manner.

The compounds listed in Tables 4 to 8 below can likewise be prepared in a similar manner.

                                      TABLE 1     __________________________________________________________________________                                                  physical data,                                                  H-NMR  &, ppm!     No.        Example                                   mp.  ° C.!     __________________________________________________________________________      3        1 #STR14##                                1.8(2H); 2.4(6H); 3.08(2H);                                                  3.13(4H); 6.9(2H); 7.05(1H);                                                  7.12(1H); 7.3(2H)      4        2 #STR15##                                1.8(2H; 2.43(6H); 3.1(2H);                                                  3.18(4H); 7.1(1H); 7.25(4H);                                                  7.35(1H)      5        3 #STR16##                                191-194      6        4 #STR17##                                140-143      7        5 #STR18##                                117-119      8        6 #STR19##                                1.5(4H); 1.8(2H); 2.4(2H);                                                  2.6(4H); 3.18(2H; 3.22(4H);                                                  5.1(2H); 7.1(3H); 7.3(1H)      9        7 #STR20##                                1.8(2H); 2.45(6H); 3.1(2H);                                                  3.15(4H); 6.55(1H; 6.75(2H);                                                  7.2(1H); 7.3(2H)     10        8 #STR21##                                1.25(3H); 1.5(4H); 1.78(2H);                                                  2.4(2H); 2.6(6H); 3.2(6H);                                                  5.1(2H); 6.75(3H); 7.2(1H)     11        9 #STR22##                                1.3(9H); 1.5(4H); 1.8(2H);                                                  2.4(2H); 2.6(4H); 3.2(6H);                                                  5.25(2H); 6.75(1H);                                                  6.95(1H); 7.0(1H); 7.21(1H)     12        0 #STR23##                                1.4(3H); 1.5(4H); 1.8(2H);                                                  2.35(2H); 2.55(4H);                                                  3.18(6H); 4.0(2H); 5.2(2H);                                                  6.4(1H); 6.48(1H); 6.53(1H);                                                  7.15(1H)     13        1 #STR24##                                1.82(2H); 2.45(6H); 3.1(2H);                                                  3.2(4H); 6.85(1H); 6.95(2H);                                                  7.3(2H)     14        2 #STR25##                                146-149     15        3 #STR26##                                1.4(4H); 1.65(2H); 2.25(2H);                                                  2.4(4H); 3.05(2H); 3.2(4H);                                                  6.82(1H); 6.95(2H); 7.3(2H)     16        4 #STR27##                                96-110     17        5 #STR28##                                2.0(2H; 2.48(3H); 2.51(2H);                                                  2.58(4H); 3.2(6H); 5.38(2H);                                                  6.75(2H); 6.82(1H);                                                  7.17(1H)     18        6 #STR29##                                1.5(4H); 1.8(2H); 2.4(2H);                                                  2.48(3H); 2.6(4H); 3.15(6H);                                                  5.2(2H); 6.75(2H); 6.82(1H);                                                  7.2(1H)     19        7 #STR30##                                1.7(2H); 1.8(2H); 2.4(2H);                                                  2.6(4H); 3.05(3H); 3.15(2H);                                                  3.22(4H); 5.7(1H); 7.1(3H);                                                  7.35(1H)     20        8 #STR31##                                1.55(4H); 1.8(2H); 2.4(2H);                                                  2.6(4H); 3.2(2H); 3.25(4H);                                                  5.15(2H); 6.6(1H); 7.0(2H);                                                  7.03(1H); 7.32(1H)     21        9 #STR32##                                2.0(2H); 2.55(2H); 2.6(4H);                                                  3.22(4H) 3.3(2H); 7.1(3H);                                                  7.22(1H); 7.35(1H); 7.7(1H)     22        0 #STR33##                                1.2(6H); 1.95(2H); 2.5(2H);                                                  2.6(4H); 2.85(1H); 3.15(6H);                                                  6.05(2H); 6.75(2H); 6.8(1H);                                                  6.18(1H)     23        1 #STR34##                                170-175     24        2 #STR35##                                220-222 (Hydrochloride)     25        3 #STR36##                                2.08(2H); 2.55(2H); 2.6(4H);                                                  3.25(4H); 3.45(2H); 7.1(3H),                                                  7.3(1H); 9.0(1H)     26        4 #STR37##                                1.8(2H); 2.5(2H); 2.6(4H);                                                  2.7(2H); 3.22(4H); 5.6(2H);                                                  7.05(4H); 7.35(1H)     27        5 #STR38##                                106-112     28        6 #STR39##                                1.85(2H); 2.5(2H); 2.6(2H);                                                  3.1(4H); 3.35(2H); 6.3(1H);                                                  7.3(2H); 7.6(2H); 7.75(2H)     29        7 #STR40##                                1.45(4H); 1.68(2H); 2.4(2H);                                                  2.6(2H); 3.05(4H); 3.3(2H);                                                  6.3(1H); 7.28(2H); 7.6(2H);                                                  7.75(2H)     30        8 #STR41##                                128-130 (Dihydrochloride)     31        9 #STR42##                                1.83(2H); 2.43(2H); 2.5(4H);                                                  3.1(2H); 3.15(4H), 6.92(1H);                                                  6.96(1H); 7.1(2H); 7.3(2H);                                                  7.35(1H)     32        0 #STR43##                                129-130     33        1 #STR44##                                2.55(2H); 2.75(3H);                                                  3.25(2H); 3.45(2H); 3.7(8H);                                                  7.05(1H); 7.13(1H);                                                  7.19(1H); 7.4(1H);                                                  (Dihydrochloride)     34        2 #STR45##                                2.0(2H); 2.55(2H); 2.6(4H);                                                  3.05(3H); 3.2(6H); 7.1(3H);                                                  7.35(1H)     35        3 #STR46##                                1.6(4H); 2.3(2H); 2.5(4H);                                                  3.05(2H); 3.2(4H); 7.02(1H);                                                  7.1(1H); 7.2(1H); 7.3(2H);                                                  7.4(1H)     36        4 #STR47##                                1.45(4H); 1.65(2H); 2.3(2H);                                                  2.5(4H); 3.05(2H); 3.2(4H);                                                  7.05(1H); 7.15(1H); 7.2(1H);                                                  7.3(2H); 7.4(1H)     37        5 #STR48##                                120     38        6 #STR49##                                188-190 (Trihydrachloride)     39        7 #STR50##                                107-110     40        8 #STR51##                                131-132     41        9 #STR52##                                134-135     42        0 #STR53##                                108-109     43        1 #STR54##                                140-141     44        2 #STR55##                                137-139     45        3 #STR56##                                127-130     46        4 #STR57##                                139-142     __________________________________________________________________________

                  TABLE 2     ______________________________________     1 #STR58##     Ex. No.            R.sup.1                   R.sup.6 A              mp.  °C.!     ______________________________________     47     NH.sub.2                   CF.sub.3                           S--CH.sub.2 C(CH.sub.3)═CHCH.sub.2 --                                          152-154°     48     NH.sub.2                   CF.sub.3                           S--(CH.sub.2).sub.9 --                                          118-123°     49     NH.sub.2                   iProp   S--(CH.sub.2).sub.7 --                                           98-101°     50     NH.sub.2                   CN      S--(CH.sub.2).sub.7 --                                          162-166°     51     NH.sub.2                   CN      S--(CH.sub.2).sub.8 --                                           98-102°     52     NH.sub.2                   iProp   S--(CH.sub.2).sub.8 --                                          95-99°     ______________________________________

                  TABLE 3     ______________________________________     2 #STR59##     Ex.     No.  R.sup.1                 R.sup.6 R.sup.8                              D   A            mp.  °C.!     ______________________________________     53   NH.sub.2                 CF.sub.3                         H    CH  S--CH.sub.2 CH═CHCH.sub.2 --                                               116-119°     54   NH.sub.2                 1-      CH.sub.3                              N   S--(CH.sub.2).sub.5 --                                               145-148°                 Pyrrolyl     55   NH.sub.2                 tBut    CF.sub.3                              N   S--(CH.sub.2).sub.3 --                                               128-130°     56   NH.sub.2                 1-      CH.sub.3                              N   S--(CH.sub.2).sub.3 --                                               130-132°                 Pyrrolyl     57   NH.sub.2                 iProp   CF.sub.3                              N   S--(CH.sub.2).sub.3 --                                               109-111°     58   NH.sub.2                 tBut    tBut N   S--(CH.sub.2).sub.3 --                                               142-145°     ______________________________________

                                      TABLE 4     __________________________________________________________________________     3 #STR60##     Ex. No.         R1  R5  R6 R7  R8   R9 X--Y A     __________________________________________________________________________     59  NH.sub.2             H   tBut                    H   Me   H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     60  NH.sub.2             H   tBut                    H   Ph   H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     61  NH.sub.2             H   tBut                    H   1-Pyrrolyl                             H  CH.sub.2 --N                                     NH--(CH.sub.2).sub.3 --     62  NH.sub.2             H   iProp                    H   2-Napht                             H  CH═C                                     --CH.sub.2 --(CH.sub.2).sub.3 --     63  NH.sub.2             H   Et H   tBut H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     64  NH.sub.2             OMe tBut                    H   H    H  CH═C                                     --CH.sub.2 --(CH.sub.2).sub.3 --     65  NH.sub.2             OMe CF.sub.3                    H   H    H  CH═C                                     S--(CH.sub.2).sub.3 --     66  NH.sub.2             H   CF.sub.3                    H   tBut H  CH.sub.2 --N                                     NH--(CH.sub.2).sub.3 --     67  NH.sub.2             OiProp                 iProp                    H   H    H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     68  NH.sub.2             H   H  CN  tBut H  CH.sub.2 --N                                     O--(CH.sub.2).sub.3 --     69  NH.sub.2             H   H  F   tBut H  CH═C                                     S--(CH.sub.2).sub.3 --     70  NH.sub.2             H   H  Cl  iProp                             H  CH.sub.2 --N                                     --CH.sub.2 --(CH.sub.2).sub.3 --     71  NH.sub.2             H   tBut                    H   H    OMe                                CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     72  NH.sub.2             OMe tBut                    H   tBut H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     73  NH.sub.2             OMe tBut                    H   CF.sub.3                             H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     74  NH.sub.2             OMe CF.sub.3                    H   tBut H  CH.sub.2 --N                                     NH--(CH.sub.2).sub.3 --     75  NH.sub.2             H   nProp                    CN  tBut H  CH═C                                     --CH.sub.2 --(CH.sub.2).sub.3 --     76  NH.sub.2             H   CF.sub.3                    CN  iProp                             H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     77  NH.sub.2             H   Ph C═CH                        tBut H  CH═C                                     --CH.sub.2 --(CH.sub.2).sub.3 --     78  NH.sub.2             OMe tBut                    CN  H    H  CH═C                                     S--(CH.sub.2).sub.3 --     79  NH.sub.2             H   tBut                    CN  CF.sub.3                             OMe                                CH.sub.2 --N                                     NH--(CH.sub.2).sub.3 --     80  NH.sub.2             OMe nProp                    F   tBut H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     81  NH.sub.2             H   Ph CN  tBut Me CH.sub.2 --N                                     O--(CH.sub.2).sub.3 --     82  NH.sub.2             OMe tBut                    F   H    H  CH═C                                     S--(CH.sub.2).sub.3 --     83  NH.sub.2             H   iProp                    H   H    OMe                                CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     84  NH.sub.2             H   tBut                    H   Me   H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     85  NH.sub.2             H   tBut                    H   Ph   H  CH.sub.2 --N                                     NH--(CH.sub.2).sub.4 --     86  NH.sub.2             H   tBut                    H   1-Pyrrolyl                             H  CH.sub.2 --N                                     S--(CH.sub.2).sub.4 --     87  NH.sub.2             H   iProp                    H   2-Napht                             H  CH.sub.2 --N                                     --CH.sub.2 --(CH.sub.2).sub.3 --     88  NH.sub.2             H   Et H   tBut H  CH.sub.2 --N                                     S--(CH.sub.2).sub.5 --     89  NH.sub.2             OMe tBut                    H   H    H  CH.sub.2 --N                                     O--(CH.sub.2).sub.5 --     90  NH.sub.2             OMe CF.sub.3                    H   H    H  CH═C                                     NH--(CH.sub.2).sub.4 --     91  NH.sub.2             H   CF.sub.3                    H   tBut H  CH.sub.2 --N                                     --CH.sub.2 --(CH.sub.2).sub.4 --     92  NH.sub.2             OiProp                 iProp                    H   H    H  CH═C                                     S--(CH.sub.2).sub.3 --     93  NH.sub.2             H   H  CN  tBut H  CH.sub.2 --N                                     NH--(CH.sub.2).sub.3 --     94  NH.sub.2             H   H  F   tBut H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     95  NH.sub.2             H   H  Cl  iProp                             H  CH═C                                     --CH.sub.2 --(CH.sub.2).sub.3 --     96  NH.sub.2             H   tBut                    H   H    OMe                                CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     97  NH.sub.2             OMe tBut                    H   tBut H  CH.sub.2 --N                                     S--(CH.sub.2).sub.4 --     98  NH.sub.2             OMe tBut                    H   CF.sub.3                             H  CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     99  NH.sub.2             OMe CF.sub.3                    H   tBut H  CH.sub.2 --N                                     NH--(CH.sub.2).sub.5 --     100 NH.sub.2             H   nProp                    CN  tBut H  CH═C                                     --CH.sub.2 --(CH.sub.2).sub.3 --     101 NH.sub.2             H   CF.sub.3                    CN  iProp                             H  CH.sub.2 --N                                     S--(CH.sub.2).sub.4 --     102 NH.sub.2             H   Ph C═CH                        tBut H  CH═C                                     --CH.sub.2 --(CH.sub.2).sub.3 --     103 NH.sub.2             OMe tBut                    CN  H    H  CH═C                                     S--(CH.sub.2).sub.6 --     104 NH.sub.2             H   tBut                    CN  CF.sub.3                             OMe                                CH.sub.2 --N                                     NH--(CH.sub.2).sub.3 --     105 NH.sub.2             OMe nProp                    F   tBut H  CH.sub.2 --N                                     S--(CH.sub.2).sub.5 --     106 NH.sub.2             H   Ph CN  tBut Me CH.sub.2 --N                                     O--(CH.sub.2).sub.3 --     107 NH.sub.2             OMe tBut                    F   H    H  CH═C                                     S--(CH.sub.2).sub.4 --     108 NH.sub.2             H   iProp                    H   H    OMe                                CH.sub.2 --N                                     S--(CH.sub.2).sub.3 --     109 NHMe             H   tBut                    H   Me   H  CH.sub.2 --N                                     S--CH.sub.2 --CH═CH--CH.sub.2 --     110 NHMe             H   tBut                    H   Ph   H  CH.sub.2 --N                                     --CH.sub.2 --CH.sub.2 --CH═CH--CH.sub.                                     2 --     111 NHMe             H   tBut                    H   1-Pyrrolyl                             H  CH.sub.2 --N                                     S--CH.sub.2 --CH═CH--CH.sub.2 --     112 NHMe             H   iProp                    H   2-Napht                             H  CH.sub.2 --N                                     NH--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.                                     2 --     113 NHMe             H   Et H   tBut H  CH.sub.2 --N                                     S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2                                      --     114 OH  OMe tBut                    H   H    H  CH.sub.2 --N                                     --CH.sub.2 --CH.sub.2 --C(CH.sub.3)═CH                                     --CH.sub.2 --     115 OH  OMe CF.sub.3                    H   H    H  CH.sub.3 --N                                     NH--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.                                     2 --     116 OH  H   CF.sub.3                    H   tBut H  CH.sub.2 --N                                     S--CH.sub.2 --CH═CH--CH.sub.2 --     117 OH  OiProp                 iProp                    H   H    H  CH═C                                     --CH.sub.2 --CH.sub.2 --CH═CH--CH.sub.                                     2 --     118 OMe H   H  CN  tBut H  CH═C                                     --CH.sub.2 --CH.sub.2 --CH═CH--CH.sub.                                     2 --     119 OMe H   H  F   tBut H  CH═C                                     S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2                                      --     120 OMe H   H  Cl  iProp                             H  CH═C                                     O--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2                                      --     121 OMe H   tBut                    H   H    OMe                                CH═C                                     NH--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.                                     2 --     122 NHMe             OMe tBut                    H   tBut H  CH.sub.2 --N                                     S--CH.sub.2 --CH═CH--CH.sub.2 --     123 NHMe             OMe tBut                    H   CF.sub.3                             H  CH.sub.2 --N                                     --CH.sub.2 --CH.sub.2 --CH═CH--CH.sub.                                     2 --     124 NHMe             OMe CF.sub.3                    H   tBut H  CH.sub.2 --N                                     S--CH.sub.2 --CH═CH--CH.sub.2 --     125 NHMe             H   nProp                    CN  tBut H  CH.sub.2 --N                                     NH--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.                                     2 --     126 NHMe             H   CF.sub.3                    CN  iProp                             H  CH.sub.2 --N                                     S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2                                      --     127 OH  H   Ph C═CH                        tBut H  CH.sub.2 --N                                     --CH.sub.2 --CH.sub.2 --C(CH.sub.3)═CH                                     --CH.sub.2 --     128 OH  OMe tBut                    CN  H    H  CH.sub.2 --N                                     NH--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.                                     2 --     129 OH  H   tBut                    CN  CF.sub.3                             OMe                                CH.sub.2 --N                                     S--CH.sub.2 --CH═CH--CH.sub.2 --     130 OH  OMe nProp                    F   tBut H  CH═C                                     --CH.sub.2 --CH.sub.2 --CH═CH--CH.sub.                                     2 --     131 OMe H   Ph CN  tBut Me CH═C                                     --CH.sub.2 --CH.sub.2 --CH═CH--CH.sub.                                     2 --     132 OMe OMe tBut                    F   H    H  CH═C                                     S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2                                      --     133 OMe H   iProp                    H   H    OMe                                CH═C                                     S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2                                      --     __________________________________________________________________________

                                      TABLE 5     __________________________________________________________________________     4 #STR61##     Ex. No.         R1  R6 R7  R8 R9 X--Y A     __________________________________________________________________________     134 NH.sub.2             tBut                H   tBut                       H  CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     135 OH  tBut                CN  H  H  CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     136 NHMe             tBut                H   H  OMe                          CH.sub.2 --N                               NH--CH.sub.2 --CH═CH--CH.sub.2 --     137 NH.sub.2             H  CN  tBut                       H  CH═C                               --CH.sub.2 --CH.sub.2 --C(CH.sub.3)═CH--CH.s                               ub.2 --     138 NHMe             CF.sub.3                H   tBut                       H  CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     139 NH.sub.2             nProp                H   iProp                       H  CH═C                               --CH.sub.2 --(CH.sub.2).sub.3 --     140 NHMe             H  H   iProp                       OMe                          CH═C                               S--(CH.sub.2).sub.3 --     141 NH.sub.2             tBut                H   tBut                       H  CH.sub.2 --N                               NH--CH.sub.2 --CH═CH--CH.sub.2 --     142 NH.sub.2             tBut                CN  H  H  CH.sub.2 --N                               S--(CH.sub.2).sub.4 --     143 NHMe             tBut                H   H  OMe                          CH.sub.2 --N                               O--(CH.sub.2).sub.3 --     144 OH  H  CN  tBut                       H  CH═C                               S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2 --     145 NH.sub.2             CF.sub.3                H   tBut                       H  CH.sub.2 --N                               --CH.sub.2 --(CH.sub.2).sub.3 --     146 NH.sub.2             nProp                H   iProp                       H  CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     147 NH.sub.2             nProp                CN  tBut                       H  CH.sub.2 --N                               S--(CH.sub.2).sub.4 --     148 OH  CF.sub.3                CN  iProp                       H  CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     149 NHMe             Ph C═CH                    tBut                       H  CH.sub.2 --N                               NH--CH.sub.2 --CH═CH--CH.sub.2 --     150 NH.sub.2             tBut                CN  tBut                       H  CH═C                               --CH.sub.2 --CH.sub.2 --C(CH.sub.3)═CH--CH.s                               ub.2 --     151 NHMe             tBut                H   nProp                       OMe                          CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     152 NH.sub.2             Ph H   tBut                       OMe                          CH═C                               --CH.sub.2 --(CH.sub.2).sub.5 --     153 NHMe             CF.sub.3                H   tBut                       OMe                          CH═C                               S--(CH.sub.2).sub.3 --     154 NH.sub.2             tBut                F   H  Me CH.sub.2 --N                               NH--CH.sub.2 --CH═CH--CH.sub.2 --     155 NH.sub.2             nProp                CN  tBut                       Me CH.sub.2 --N                               S--CH.sub.2 --CH═CH--CH.sub.2 --     156 OH  nProp                C═CH                    tBut                       OMe                          CH═C                               --CH.sub.2 --CH.sub.2 --C(CH.sub.3)═CH--CH.s                               ub.2 --     157 NHMe             tBut                CN  H  OMe                          CH.sub.2 --N                               S--(CH.sub.2).sub.4 --     158 OH  H  H   iProp                       OMe                          CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     __________________________________________________________________________

                                      TABLE 6     __________________________________________________________________________     5 #STR62##     Ex. No.         R1  R5 R7                  R8 R9 X--Y A     __________________________________________________________________________     159 NH.sub.2             OMe                H tBut                     H  CH.sub.2 --N                             S--(CH.sub.2).sub.3 --     160 OH  OMe                H CF.sub.3                     H  CH.sub.2 --N                             S--(CH.sub.2).sub.3 --     161 NHMe             OMe                H tBut                     H  CH.sub.2 --N                             NH--CH.sub.2 --CH═CH--CH.sub.2 --     162 NH.sub.2             H  CN                  tBut                     H  CH═C                             --CH.sub.2 --CH.sub.2 --C(CH.sub.3)═CH--CH.sub                             .2 --     163 NHMe             H  F tBut                     H  CH.sub.2 --N                             S--(CH.sub.2).sub.3 --     164 NH.sub.2             Me Cl                  iProp                     H  CH═C                             --CH.sub.2 --(CH.sub.2).sub.3 --     165 NHMe             H  H iProp                     OMe                        CH═C                             S--(CH.sub.2).sub.3 --     166 NH.sub.2             H  H tBut                     OMe                        CH.sub.2 --N                             NH--CH.sub.2 --CH═CH--CH.sub.2 --     167 NH.sub.2             CN H CF.sub.3                     H  CH.sub.2 --N                             S--(CH.sub.2).sub.4 --     168 NHMe             H  CN                  H  OMe                        CH.sub.2 --N                             O--(CH.sub.2).sub.3 --     169 OH  H  H tBut                     OEt                        CH═C                             S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2 --     170 NH.sub.2             H  CN                  tBut                     H  CH.sub.2 --N                             --CH.sub.2 --(CH.sub.2).sub.3 --     171 NH.sub.2             Me H iProp                     H  CH.sub.2 --N                             S--(CH.sub.2).sub.3 --     172 NH.sub.2             OMe                CN                  tBut                     H  CH.sub.2 --N                             S--(CH.sub.2).sub.4 --     173 NH.sub.2             OMe                Me                  tBut                     H  CH.sub.2 --N                             S--(CH.sub.2).sub.3 --     174 NHMe             H  CN                  tBut                     OMe                        CH.sub.2 --N                             NH--CH.sub.2 --CH═CH--CH.sub.2 --     175 NH.sub.2             Me H tBut                     OMe                        CH═C                             --CH.sub.2 --CH.sub.2 --C(CH.sub.3)═CH--CH.sub                             .2 --     176 NH.sub.2             H  Cl                  CF.sub.3                     Me CH.sub.2 --N                             S--(CH.sub.2).sub.5 --     177 NHMe             OMe                CN                  tBut                     Me CH═C                             --CH.sub.2 --(CH.sub.2).sub.3 --     178 OH  Me Me                  iProp                     Me CH═C                             S--(CH.sub.2).sub.4 --     179 OH  OMe                H iProp                     H  CH.sub.2 --N                             S--(CH.sub.2).sub.3 --     __________________________________________________________________________

                                      TABLE 7     __________________________________________________________________________     6 #STR63##     Ex. No.         R1  R5 R6  R8   R9 X--Y A     __________________________________________________________________________     180 NH.sub.2             H  tBut                    tBut H  CH.sub.2 --N                                 S--(CH.sub.2).sub.3 --     181 OH  H  tBut                    Ph   H  CH.sub.2 --N                                 S--(CH.sub.2).sub.3 --     182 NHMe             H  tBut                    1-Pyrrolyl                         H  CH.sub.2 --N                                 NH--CH.sub.2 --CH═CH--CH.sub.2 --     183 NH.sub.2             H  nPropyl                    tBut H  CH═C                                 --CH.sub.2 --CH.sub.2 --C(CH.sub.3)═CH--CH                                 .sub.2 --     184 NHMe             H  CF.sub.3                    tBut H  CH.sub.2 --N                                 S--(CH.sub.2).sub.3 --     185 NH.sub.2             H  2-Napht                    tBut H  CH═C                                 --CH.sub.2 --(CH.sub.2).sub.3 --     186 NHMe             OMe                tBut                    H    H  CH═C                                 S--(CH.sub.2).sub.3 --     187 NH.sub.2             OMe                iProp                    H    H  CH.sub.2 --N                                 NH--CH.sub.2 --CH═CH--CH.sub.2 --     188 NH.sub.2             OMe                H   CF.sub.3                         H  CH.sub.2 --N                                 S--(CH.sub.2).sub.4 --     189 NHMe             H  tBut                    H    OMe                            CH.sub.2 --N                                 O--(CH.sub.2).sub.3 --     190 OH  H  iProp                    H    Me CH═C                                 S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2                                 --     191 NH.sub.2             CN tBut                    H    H  CH.sub.2 --N                                 --CH.sub.2 --(CH.sub.2).sub.3 --     192 NH.sub.2             H  H   CF.sub.3                         Me CH.sub.2 --N                                 S--(CH.sub.2).sub.3 --     193 NHMe             OMe                tBut                    iProp                         H  CH.sub.2 --N                                 S--(CH.sub.2).sub.4 --     194 OH  OMe                CF.sub.3                    tBut H  CH.sub.2 --N                                 NH--CH.sub.2 --CH═CH--CH.sub.2 --     195 NH.sub.2             Me tBut                    nProp                         H  CH═C                                 --CH.sub.2 --CH.sub.2 --C(CH.sub.3)═CH--CH                                 .sub.2 --     196 NH.sub.2             Me tBut                    H    OMe                            CH.sub.2 --N                                 S--(CH.sub.2).sub.5 --     197 NH.sub.2             OMe                tBut                    tBut OMe                            CH═C                                 --CH.sub.2 --(CH.sub.2).sub.3 --     198 NH.sub.2             Me CF.sub.3                    tBut OMe                            CH═C                                 S--(CH.sub.2).sub.4 --     199 OH  H  nProp                    tBut H  CH.sub.2 --N                                 S--(CH.sub.2).sub.3 --     __________________________________________________________________________

                                      TABLE 8     __________________________________________________________________________     7 #STR64##     Ex. No.         R1   R6  R8   R9 X--Y A     __________________________________________________________________________     200 NH.sub.2              tBut                  Ph   H  CH.sub.2 --N                               --CH.sub.2 --(CH.sub.2).sub.3 --     201 NH.sub.2              tBut                  2-Napht                       H  CH.sub.2 --N                               S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2 --     202 NH.sub.2              tBut                  1-Pyrrolyl                       H  CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     203 NHMe tBut                  cHex H  CH═C                               --CH.sub.2 --(CH.sub.2).sub.3 --     204 NH.sub.2              tBut                  nHex H  CH.sub.2 --N                               S--(CH.sub.2).sub.5 --     205 NH.sub.2              tBut                  H    OMe                          CH.sub.2 --N                               --CH.sub.2 --(CH.sub.2).sub.3 --     206 NHMe iProp                  H    OMe                          CH.sub.2 --N                               S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2 --     207 NH.sub.2              H   CH.sub.3                       OMe                          CH═C                               NH--(CH.sub.2).sub.3 --     208 NH.sub.2              H   iProp                       OMe                          CH.sub.2 --N                               O--CH.sub.2 --CH═CH--CH.sub.2 --     209 NH.sub.2              tBut                  tBut OMe                          CH.sub.2 --N                               --CH.sub.2 --(CH.sub.2).sub.3 --     210 NHMe tBut                  iProp                       OMe                          CH.sub.2 --N                               S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2 --     211 NH.sub.2              Ph  tBut Cl CH.sub.2 --N                               S--(CH.sub.2).sub.4 --     212 NH.sub.2              2-Napht                  tBut Me CH═C                               --CH.sub.2 --(CH.sub.2).sub.3 --     213 NH.sub.2              tBut                  CF.sub.3                       OMe                          CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     214 NH.sub.2              tBut                  H    CH.sub.3                          CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     215 NH.sub.2              tBut                  Ph   H  CH.sub.2 --N                               S--(CH.sub.2).sub.3 --     216 NH.sub.2              tBut                  2-Napht                       H  CH═C                               NH--(CH.sub.2).sub.3 --     217 NH.sub.2              tBut                  1-Pyrrolyl                       H  CH.sub.2 --N                               O--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2 --     218 NH.sub.2              tBut                  cHex H  CH.sub.2 --N                               --CH.sub.2 --(CH.sub.2).sub.3 --     219 OH   tBut                  nHex H  CH.sub.2 --N                               S--(CH.sub.2).sub.4 --     220 OH   tBut                  H    OMe                          CH═C                               S--(CH.sub.2).sub.4 --     221 OMe  iProp                  H    OMe                          CH.sub.2 --N                               --CH.sub.2 --CH.sub.2 --CH═CH--CH.sub.2 --     222 OMe  H   CH.sub.3                       OMe                          CH.sub.2 --N                               --CH.sub.2 --(CH.sub.2).sub.3 --     223 NCH.sub.2 Ph              H   iProp                       OMe                          CH.sub.2 --N                               S--CH.sub.2 --C(CH.sub.3)═CH--CH.sub.2 --     224 OH   tBut                  tBut OMe                          CH.sub.2 --N                               --CH.sub.2 --(CH.sub.2).sub.4 --     225 OH   tBut                  iProp                       OMe                          CH.sub.2 --N                               S--CH.sub.2 --CH═CH--CH.sub.2 --     226 OMe  Ph  tBut Cl CH.sub.2 --N                               S--(CH.sub.2).sub.5 --     227 OMe  2-Napht                  tBut Me CH═C                               --CH.sub.2 --(CH.sub.2).sub.3 --     228 NCH.sub.2 Ph              tBut                  CF.sub.3                       OMe                          CH.sub.2 --N                               S--(CH.sub.2).sub.4 --     229 NHMe tBut                  H    CH.sub.3                          CH═C                               S--(CH.sub.2).sub.3 --     __________________________________________________________________________

Examples of Pharmaceutical forms:

A) Tablets

Tablets of the following composition were compressed in a tabletting machine in a conventional manner

40 mg of substance of Example 1

120 mg of corn starch

13.5 mg of gelatin

45 mg of lactose

2.25 mg of Aerosil® (chemically pure silica in submicroscopically fine dispersion)

6.75 mg of potato starch (as 6% strength paste)

B) Sugar-coated tablets

20 mg of substance of Example 4

60 mg of core composition

70 mg of sugar-coating composition

The core composition comprises 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer. The sugar-coating composition comprises 5 parts of sucrose, lacuna! parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets produced in this way are subsequently provided with an enteric coating.

Biological investigations - receptor-binding studies

1) D₃ binding assay

Cloned human D₃ receptor-expressing CCL 1.3 mouse fibroblasts obtained from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2418 USA, were used for the binding studies.

Cell preparation

The D₃ -expressing cells were grown in RPMI-1640 containing 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U/ml penicillin and 0.2% streptomycin (GIBCO BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Neutralization with medium was then carried out, and the cells were collected by centrifugation at 300×g. To lyze the cells, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4, with 10% glycerol) and then incubated in a concentration of 10⁷ cells/ml of lysis buffer at 4° C. for 30 min. The cells were centrifuged at 200×g for 10 min and the pellet was stored in liquid nitrogen.

Binding assays

For the D₃ receptor-binding assay, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4, with 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2mM MgCl₂, 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA) in a concentration of about 10⁶ cells/250 μl of assay mixture and incubated at 30° C. with 0.1 nM ¹²⁵ iodosulpiride in the presence and absence of test substance. The non-specific binding was determined using 10⁻⁶ M spiperone.

After 60 min, the free and the bound radioligand was separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway), and the filters were washed with ice-cold tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K_(i) values were determined by non-linear regression analysis using the LIGAND program.

2) D₂ binding assay

Membrane preparation

a) Nucleus caudatus (bovine)

Nucleus caudatus was removed from bovine brain and washed with ice-cold 0.32 M sucrose solution. After determination of the weight, the material was comminuted and homogenized in 5-10 volumes of sucrose solution using a Potter-Evehjem sic! homogenizer (500 rpm). The homogenate was centrifuged at 3,000×g for 15 minutes (4° C.), and the resulting supernatant was subjected to another 15-minute centrifugation at 40,000×g. The residue was then washed twice, by resuspension and centrifugation, with 50 mM tris-HCl, pH 7.4. The membranes were stored in liquid nitrogen until used.

b) Striatum (rat)

Striati from Sprague-Dawley rats were washed in ice-cold 0.32 M sucrose solution. After determination of the weight, the parts of the brain were homogenized in 5-10 volumes of sucrose solution using a Potter-Elvehjem homogenizer (500 rpm). The homogenate was centrifuged at 40,000×g for 10 minutes (4° C.), and then the residue was washed several times, by resuspension and centrifugation, with 50 mM tris-HCl, 0.1 mM EDTA and 0.01% ascorbic acid (pH 7.4). The washed residue was resuspended in the abovementioned buffer and incubated at 37° C. for 20 minutes (to break down the endogenous dopamine). The membranes were then washed twice with buffer and portions were frozen in liquid nitrogen. The membrane preparation was stable for a maximum of one week.

Binding assay

a) ³ H-Spiperone (D_(2low))

Nucleus caudatus membranes were taken up in incubation buffer (mM: tris-HCl 50, NaCl 120, KCl 5, MgCl₂ 1, CaCl₂ 2, pH 7.4). Various mixtures, each of 1 ml, were prepared:

Total binding: 400 μg of membranes+0.2 nmol/l ³ H-spiperone (Du Pont de Nemours, NET-565).

Non-specific binding: as mixtures for total binding+10 μM (+)-butaclamol.

Test substance: as mixtures for total binding+increasing concentrations of test substance.

After incubation at 25° C. for 60 minutes, the mixtures were filtered through GF/B glass fibre filters (Whatman, England) on a Skatron cell collector (from Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K_(i) values were determined by non-linear regression analysis using the LIGAND program or by conversion of the IC₅₀ values using the formula of Cheng and Prusoff.

b) ³ H-ADTN (D_(2high))

Striatum membranes were taken up in incubation buffer (50 mM tris-HCl, pH 7.4, 1 mM MnCl₂ and 0.1% ascorbic acid).

Various mixtures, each of 1 ml, were prepared.

Total binding: 300 μg wet weight+1 nM ³ H-ADTN (Du Pont de Nemours, customer synthesis)+100 nM SCH 23390 (occupation of D₁ receptors).

Non-specific bindings: as mixtures for total binding+50 nM spiperone.

Test substance: as mixtures for total binding+increasing concentrations of test substance.

After incubation at 25° C. for 60 minutes, the mixtures were filtered through GF/B glass fibre filters (Whatman, England) on a Skatron cell collector (from Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM tris-HCl buffer, pH 7.4.

The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The evaluation took place as under a).

In these assays, the compounds according to the invention show very good affinities and high selectivities for the D₃ receptor. The results obtained for representative compounds are compiled in the following Table 9.

                  TABLE 9     ______________________________________     Receptor binding              D.sub.3       D.sub.2     Example  .sup.125 I-sulpiride                            .sup.3 H-spiperone                                      Selectivity     No.      K.sub.i  nM!  K.sub.i  mM!                                      K.sub.i D.sub.2 /K.sub.i D.sub.3     ______________________________________      2       1.4            65       46     13       0.6            25       41     16       10.9          402       36     23       6.3           200       31     49       6.5           560       86     51       8.3           500       62     53        2.95         145       50     56       27.0          3,500     70     58       1.7           225       132     ______________________________________ 

We claim:
 1. A method for treating disorders which respond to dopamine D₃ receptor antagonists or agonists which comprises administering to a person requiring such treatment an effective amount of a member selected from the group consisting of thiazole and thiadiazole compounds of the formula I: ##STR65## where A is a straight-chain or branched C₃ -C₁₄ -alkylene group which comprises at least one group selected from O, S, and NR,B is a radical of the formula: ##STR66## R¹ is H, NR² R³, or C₁ -C₈ -alkyl; R² is H or C₁ -C₈ -alkyl, which is unsubstituted or substituted by OH; R³ has the meanings indicated for R² ; X is N; Ar is phenyl, pyridyl or pyrimidyl where Ar may have one or two substituents which are selected, independently of one another, from OR³, C₁ -C₈ -alkyl, halogen, CN, NO₂, CF₃, CHF₂, phenyl, and a 5-membered heterocyclic aromatic ring having 1 or 2 hetero atoms selected from O, S and N,and the salts thereof with physiologically tolerated acids.
 2. A method as claimed in claim 1 which comprises administering a member selected from the group consisting of compounds of the formula I where R¹ is H, or NR² R³, where R² and R³ are, independently of one another, H or C₁ -C₈ -alkyl; and A is C₃ -C₁₂ -alkylene which comprises at least one group selected from O, S, and NR³.
 3. A method as claimed in claim 1 of compounds of the formula I whereB is ##STR67##
 4. A method as claimed in claim 1 of compound of the formula I where Ar is phenyl which has one or two substituents which are selected, independently of one another, from H, C₁ -C₈ -alkyl, phenyl, pyrrolyl, CHF₂, CF₃, halogen, NO₂, CN, OH, OC₁ -C₈ -alkyl.
 5. A method as claimed in claim 4, where Ar has one or two substituents which are in position 3 or position 3,5.
 6. A method as claimed in any of claims 1 to 5 of compounds of the formula I where Ar is pyrimidinyl which has one or two substituents which are selected, independently of one another, from H, C₁ -C₈ -alkyl, phenyl, pyrrolyl, OH, OC₁ -C₈ -alkyl, CHF₂, CF₃ and halogen.
 7. A method as claimed in claim 1 of compounds of the formula I where Ar is pyridinyl which has one or two substituents which are selected, independently of one another, from H, C₁ -C₁ -alkyl, phenyl, pyrrolyl, OH, OC₁ -C₈ -alkyl, CHF₂, CF₃, CN and halogen.
 8. A compound of the formula I: ##STR68## where A is a straight-chain or branched C₇ -C₁₄ -alkylene group which comprises a group which is selected from O, S, and NR³ and, R¹, R², R³, B and Ar have the meanings stated in claim
 1. 9. A process for preparing compounds as claimed in claim 8, which comprisesi) reacting a compound of the general formula II: ##STR69## where Y' is a conventional leaving group, with a compound of the general formula III:

    H--B--Ar

ii) to prepare a compound of the formula I where A comprises an oxygen or sulfur atom or NR³,a) reacting a compound of the general formula IV: ##STR70## where Z¹ is O, S or NR³, and A¹ is C₀ -C₁₈ -alkylene, with a compound of the general formula VI

    Y.sup.1 --A.sup.2 --B--Ar

where Y¹ has the abovementioned meanings, and A² is C₁ -C₁₄ -alkylene, where A¹ and A² together have 7 to 14 carbon atoms; and all the other substituents have the same meaning as defined in claim
 1. 10. A pharmaceutical composition containing at least one compound of the formula I as claimed in claim 8 with or without physiologically acceptable salts.
 11. A process for preparing compounds as claimed in claim 8, which comprisesi) reacting a compound of the general formula II: ##STR71## where Y¹ is a conventional leaving group, with a compound of the general formula III:

    H--B--Ar. 